The invention is in the field of medicinal chemistry. The invention relates in particular to a method of reversing local anesthesia induced by a local anesthetic and an alpha-adrenergic agonist, comprising administering an effective low dose of an alpha-adrenergic antagonist.
Local anesthesia is widely used by dentists to provide pain relief to patients during dental procedures. To provide pain relief, a drug formulation containing a local anesthetic compound such as lidocaine is injected into the gum tissue surrounding the tooth or teeth on which the dental procedure is to be performed. There are short-acting and long-lasting local anesthetic drug formulations. Short-acting local anesthetic drug formulations contain lidocaine or a related local anesthetic drug dissolved in saline or other suitable injection vehicle. Typically, local anesthesia with short-acting local anesthetics lasts approximately 20-30 minutes, which is not long enough for many dental procedures. To obtain long-lasting local anesthesia, dentists often use lidocaine or other local anesthetic formulations which, in addition to the local anesthetic drug itself, contain low concentrations of epinephrine or another adrenergic receptor agonist such as levonordefrin. More than 90% of the local anesthesia procedures performed by dentists involve local anesthetic formulations containing alpha-adrenergic receptor agonists. The vasoconstrictor is necessary because local anesthetics without vasoconstrictor are too short-acting for most dental procedures. The added epinephrine stimulates alpha-adrenergic receptors on the blood vessels in the injected tissue. This has the effect of constricting the blood vessels in the tissue. The blood vessel constriction causes the local anesthetic to stay in the tissue much longer, resulting in a large increase in the duration of the anesthetic effect (from 20 minutes for the short-acting formulation to 3-6 hours for the long-lasting formulation). A major problem with the use of epinephrine-containing local anesthetics is soft-tissue anesthesia (lip, cheek, tongue) which usually lasts many hours longer than anesthesia and analgesia of the tooth pulp. Tooth pulp anesthesia and analgesia are the desired effects of local anesthesia from a dental procedural perspective while soft-tissue anesthesia is usually an undesirable side effect. Soft tissue anesthesia results in a number of problems and inconveniences, such as a prolonged and uncomfortable feeling of numbness in and around the mouth, inability to smile, difficulty eating, drinking and swallowing, loss of productivity by missing work hours or meetings etc. Lingering soft-tissue anesthesia can be the cause of injuries due to biting of the tongue or lips. Lingering soft-tissue anesthesia can also result in loss of productivity due to missed work hours or meetings etc. Furthermore, lingering soft-tissue anesthesia is an inconvenience and it is perceived as an annoyance by many patients. Lingering soft-tissue anesthesia can lead to injury especially in children who often bite into the anesthetized tissue out of curiosity. It would therefore be desirable to have a drug that could be used at will by dentists to rapidly reverse local anesthesia after it is no longer needed.
U.S. Pat. No. 4,659,714 discloses a method of prolonging local anesthesia by coadministering a vasoconstrictor, in particular, a vasoconstrictor that acts upon the alpha-adrenergic receptor sites of the blood vessel walls. The ""714 patent also discloses the subsequent administration of an alpha-adrenergic receptor antagonist to cause reduction of the prolonged anesthesia effect. Included within the group of alpha-adrenergic receptor antagonists described in this patent are phentolamine mesylate. However, the examples make reference to the administration of xe2x80x9cphentolamine.xe2x80x9d It is much more likely that what was administered was phentolamine mesylate since phentolamine mesylate is FDA approved and readily soluble in water. In contrast, phentolamine is not FDA approved and is relatively insoluble in water.
As shown in Example 1, Table 1, 0.5-1.5 mg of xe2x80x9cphentolaminexe2x80x9d was administered to groups of patients which were pretreated with lignocaine admixed with epinephrine. The results in Table 1 show a reduction in the duration of anesthesia with increasing amounts of xe2x80x9cphentolamine.xe2x80x9d In Example 2, 2 mg of xe2x80x9cphentolaminexe2x80x9d was administered. In Example 3, four injections of 1 mg each (4 mg total) of xe2x80x9cphentolaminexe2x80x9d were administered. In Example 4, four injections of 1 mg each (4 mg total) of xe2x80x9cphentolaminexe2x80x9d were administered.
The drug doses of xe2x80x9cphentolaminexe2x80x9d described in the ""714 patent (0.5-4 mg) overlap the doses of phentolamine mesylate that are approved by the FDA for the systemic treatment of high blood pressure in patients with pheochromocytoma (total dose of 5 mg in a solution of 2.5-5 mg/ml). Since those doses are normally intended for systemic treatment of high blood pressure, those high dose levels can cause severe side effects when used in healthy, normal people. The package insert of the phentolamine-mesylate product states the following side effect warning: xe2x80x9cMyocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following the administration of phentolamine, usually in association with marked hypotensive episodes.xe2x80x9d Thus, the drug doses taught by the ""714 patent for the reversal of local anesthesia may cause unacceptable side effects, precluding the use of this product for anesthesia reversal in healthy normal subjects in a dentist""s office.
It has now been discovered that a highly effective local anesthesia reversal can be obtained by injections of much lower concentrations of phentolamine-mesylate than is disclosed in the ""714 patent. It has been found that a solution containing only 0.05 mg/ml of phentolamine-mesylate can rapidly reverse the effect of a local anesthetic containing an alpha adrenergic receptor agonist. This phentolamine-mesylate drug concentration is 20-100 times lower than the phentolamine-mesylate drug concentration taught by the ""714 patent. The advantage is that, at such low phentolamine-mesylate drug concentrations, no systemic side effects such as myocardial infarction and cerebrovascular spasm will be observed. This allows the safe and effective use of phentolamine-mesylate for local anesthesia reversal without causing life-threatening or other untoward side effects. Indeed, in a human clinical efficacy study using a low-concentration-formulation of phentolamine-mesylate, a highly effective anesthesia reversal was observed without any side-effects whatsoever. Thus, this invention constitutes a crucial improvement of the local anesthesia reversal method taught by the ""714 patent.
The present invention provides compositions and formulations of low concentrations of phentolamine-mesylate and other alpha adrenergic receptor antagonists and use thereof for reversing the effects of long-lasting local anesthetic agents containing alpha-adrenergic receptor agonists.
In particular, the invention relates to a method of providing local anesthesia to a mammal, comprising:
(a) administering to the mammal in need thereof an anesthetic agent and an alpha adrenergic receptor agonist to the site to be anesthetized, wherein said anesthetic agent is administered in an amount effective to provide local anesthesia and said alpha adrenergic receptor agonist is administered in an amount effective to constrict the blood vessels at the site and prolong the local anesthesia, and then
(b) administering a low dose of an alpha adrenergic receptor antagonist to said site to reduce the prolongation.
In a preferred embodiment, the invention relates to a method of providing local anesthesia to a human, comprising:
(a) administering to a human in need thereof by injection to the site to be anesthetized a solution comprising polocaine and levonordefrin, wherein said polocaine is administered in an amount effective to provide local anesthesia and said levonerdefrin is administered in an amount effective to constrict the blood vessels at the site and prolong the local anesthesia, thereby producing local anesthesia at said site,
(b) carrying out a medical procedure on the human, and then
(c) administering phentolamine mesylate at said site at a concentration of about 0.05 mg/ml or less to reduce the prolongation.
The invention also relates to a method of enhancing the survival of a tissue graft, comprising
(a) administering to a mammal undergoing a tissue graft an anesthetic agent and an alpha adrenergic receptor agonist to the site of the tissue graft, wherein said anesthetic agent is administered in an amount effective to provide local anesthesia and said alpha adrenergic receptor agonist is administered in an amount effective to constrict the blood vessels at the site and prolong the local anesthesia,
(b) performing the tissue graft procedure, and then
(c) administering an alpha adrenergic receptor antagonist to said site to reduce the prolongation and enhance the tissue graft survival.
The invention also relates to a method of providing a regional anesthetic block to a mammal, comprising:
(a) administering to the mammal in need thereof an anesthetic agent and an alpha adrenergic receptor agonist in the site to receive the anesthetic block, wherein said anesthetic agent is administered in an amount effective to provide local anesthesia and said alpha adrenergic receptor agonist is administered in an amount effective to constrict the blood vessels in the site and prolong the anesthetic block, and then
(b) administering an alpha adrenergic receptor antagonist to said site to reduce the prolongation.
The invention also relates to a kit comprising a carrier means having in close confinement therein two or more container means, wherein a first container means contains an anesthetic agent and optionally an alpha adrenergic receptor agonist and a second container means contains a low dose of an alpha adrenergic receptor antagonist.